Publications by authors named "Markus Moehler"

143 Publications

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma.

Future Oncol 2021 Apr 3;17(10):1143-1153. Epub 2021 Feb 3.

Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA 02215-5450, USA.

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. NCT04210115 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0969DOI Listing
April 2021

Any progress in informed consenting for cancer treatment? Results from a cross sectional analysis at a comprehensive cancer center.

J Cancer Res Clin Oncol 2021 Jan 9. Epub 2021 Jan 9.

Department of Internal Medicine III, Comprehensive Cancer Center, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Purpose: Informed consent is required prior to any medical procedure. In the context of cancer treatment, special efforts are needed to inform cancer patients properly about treatment, potential sequelae and alternative therapies. Little is known about the effectiveness of current informed consent strategies and patients' individual satisfaction. Given the heterogeneity in terms of age, education, sex and other factors, detailed understanding of patients' comprehension and perception is the basis for further optimization of the informed consent process, which was the aim of the current investigation.

Methods: Patients with a new cancer diagnosis and recent informed consent were asked to complete a questionnaire about satisfaction, comprehension, time management, physician-patient relationship and other items of the informed consent process. Patients were followed for 6 months and invited to complete a follow-up questionnaire.

Results: In total, 89 patients completed the first questionnaire and 52 the follow-up questionnaire. Subjective understanding was assumed high, however, this did not correlate with objective understanding. Age and education were identified as influencing factors for comprehension. 85% of the patients were satisfied with the information provided. A major gap was the information on alternative therapies. Moreover, not all patients perceived the consent dialog as such, and particularly the individual treatment intention partially remained unclear for some patients.

Conclusions: To ensure that informed consent is based on solid understanding, informed consenting must be patient-centered and consider the individual expectations, needs and abilities of cancer patients. Further studies are required to develop tailored informed consent strategies.
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http://dx.doi.org/10.1007/s00432-020-03495-1DOI Listing
January 2021

MAHOGANY: margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma.

Future Oncol 2021 Apr 2;17(10):1155-1164. Epub 2020 Dec 2.

Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Standard-of-care, first-line therapy for patients with advanced HER2+ gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2. Margetuximab is an Fc-optimized mAb that binds HER2. Retifanlimab, a humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. Tebotelimab, an IgG4κ bispecific DART molecule, binds PD-1 and lymphocyte activation gene 3 concomitantly, disrupting these nonredundant inhibitory pathways to further restore exhausted T-cell function. Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating margetuximab plus retifanlimab with/without chemotherapy and margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. NCT04082364 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1007DOI Listing
April 2021

Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100.

J Clin Oncol 2020 Nov 16:JCO2000892. Epub 2020 Nov 16.

Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti-programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC.

Patients And Methods: JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2-negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1-positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay).

Results: A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; = .1779). In the PD-L1-positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; = .6352). In an exploratory analysis of the PD-L1-positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively.

Conclusion: JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1-positive population.
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http://dx.doi.org/10.1200/JCO.20.00892DOI Listing
November 2020

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial.

Br J Cancer 2021 Feb 6;124(3):587-594. Epub 2020 Nov 6.

Division of Hematology, Oncology, and Tumor Immunology (CCM), Department of Medicine, Charité Universitaetsmedizin Berlin, Berlin, Germany.

Background: Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.

Methods: The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.

Results: Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.

Conclusions: FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS.

Gov Identifier: NCT00433927.
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http://dx.doi.org/10.1038/s41416-020-01140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851157PMC
February 2021

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

Oncol Res Treat 2020 23;43(11):628-636. Epub 2020 Oct 23.

Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Mannheim, Germany.

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%.

Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.
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http://dx.doi.org/10.1159/000510258DOI Listing
March 2021

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial.

JAMA Netw Open 2020 10 1;3(10):e2020425. Epub 2020 Oct 1.

Department of Medical Oncology, Franco-British Hospital-Fondation Cognacq-Jay, Levallois-Perret, France.

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.

Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.

Design, Setting, And Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.

Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.

Main Outcomes And Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.

Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.

Conclusions And Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.

Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).
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http://dx.doi.org/10.1001/jamanetworkopen.2020.20425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573695PMC
October 2020

Amphiregulin Expression Is a Predictive Biomarker for Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials.

Clin Cancer Res 2020 Dec 17;26(24):6559-6567. Epub 2020 Sep 17.

Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany.

Purpose: Amphiregulin () and epiregulin () are ligands of . Predictive information for anti- treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited.

Experimental Design: Ligand mRNA expression; mutations; and expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome.

Results: Of 688 patients with available material, high expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; = 0.001), and objective response rate (63.1% vs. 51.6%, = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: = 0.01, PFS: = 0.002). High mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: = 0.02, PFS: = 0.04) in WT mCRC.

Conclusions: High mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti- treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2748DOI Listing
December 2020

Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter AIO phase II trial (LICC).

Oncoimmunology 2020 08 23;9(1):1806680. Epub 2020 Aug 23.

Medical Department 1, Johannes Gutenberg University, Mainz, Germany.

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) ( = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm ( = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany.

Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.
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http://dx.doi.org/10.1080/2162402X.2020.1806680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458621PMC
August 2020

Pembrolizumab in First-line Gastric Cancer: Win, Lose, or Draw?

JAMA Oncol 2020 10;6(10):1539-1541

Department of Internal Medicine, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.1001/jamaoncol.2020.2436DOI Listing
October 2020

Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial.

Eur J Cancer 2020 09 15;137:250-259. Epub 2020 Aug 15.

Department of Medicine III, University Hospital, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Background: Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology.

Material And Methods: FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34-1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10-0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours.

Conclusions: RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.
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http://dx.doi.org/10.1016/j.ejca.2020.07.003DOI Listing
September 2020

Response to Comment on "Extended Molecular Profiling Improves Stratification and Prediction of Survival After Resection of Colorectal Liver Metastases".

Ann Surg 2020 Jul 7. Epub 2020 Jul 7.

Department of General, Visceral and Transplantation Surgery, Universitätsmedizin Mainz Mainz, Germany Department of Pathology, Universitätsmedizin Mainz Mainz, Germany Department of Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany Department of Pathology, Universita[Combining Diaeresis]tsmedizin Mainz, Mainz, Germany Department of General, Visceral and Transplantation Surgery, Universita[Combining Diaeresis]tsmedizin Mainz Mainz, Germany.

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http://dx.doi.org/10.1097/SLA.0000000000004097DOI Listing
July 2020

Predictive and prognostic value of magnesium serum level in FOLFIRI plus cetuximab or bevacizumab treated patients with stage IV colorectal cancer: results from the FIRE-3 (AIO KRK-0306) study.

Anticancer Drugs 2020 09;31(8):856-865

Division of Hematology, Oncology and Tumor Immunology (CCM), Department of Medicine, Charité - Universitaetsmedizin Berlin, Berlin.

Magnesium wasting is a frequent side effect of epidermal growth factor receptor (EGFR)-antibody treatment as magnesium-absorption mechanisms are dependent on EGFR signaling. EGFR-inhibition results in decreased renal reabsorption. There is evidence that hypomagnesemia during cetuximab treatment correlates with response. The prognostic role of hypomagnesemia during bevacizumab treatment has not been studied yet. Here, we evaluate the prognostic value of hypomagnesemia in patients with metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab as first-line therapy. A total of 391 of 752 patients of the firstline irinotecan study population had magnesium levels measured at baseline and for the first three cycles (6 weeks) of treatment. Of those, 240 had Rat Sarkoma wildtype tumors. Overall hypomagnesemia was more common in the cetuximab compared to the bevacizumab arm (80 vs. 43%, P < 0.005). During therapy, magnesium showed a time-dependent decrease to 80% of baseline in the cetuximab and to 89% in the bevacizumab arm. Whereas magnesium continued to decrease over time in the cetuximab-treated patients, it remained stable in the bevacizumab-treated. Overall response rate (ORR) was associated with higher magnesium at week 6 (20.9 vs. 79.1%, P = 0.041). Bevacizumab-treated patients with magnesium levels below the median value at week 6 had a significantly longer progression-free survival (PFS; 11.7 vs. 9.9 months, P = 0.034; hazard ratio 0.73) and a trend towards longer overall survival (OS) (29.6 vs. 23.2 months, P = 0.089; hazard ratio 0.77). Hypomagnesemia at predefined time points and magnesium nadir had no significant effect on ORR, OS and PFS in the cetuximab arm. Our data show different magnesium kinetics in patients with metastatic colorectal cancer treated with cetuximab or bevacizumab. For patients treated with cetuximab, hypomagnesemia did not have an impact on response and survival. Hypomagnesemia might have a prognostic value in bevacizumab treatment.
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http://dx.doi.org/10.1097/CAD.0000000000000965DOI Listing
September 2020

Advances in the endoscopic management of malignant biliary obstruction.

Ann Gastroenterol 2020 Jul-Aug;33(4):338-347. Epub 2020 May 25.

Johannes Gutenberg University, Mainz, Germany (Thomas Thomaidis, Visvakanth Sivanathan, Markus Moehler).

Biliary obstruction is common in pancreatobiliary malignancies and has a negative impact on the patient's quality of life, postoperative complications, and survival rates. Particularly in the last decade, there has been enormous progress regarding the diagnostic and therapeutic options in patients with malignant biliary obstruction. Endoscopy has given a new insight in this direction and novel techniques have been developed for the better characterization and treatment of malignant strictures. We herein summarize the available data on the different endoscopic techniques, and clarify their role in the diagnosis and treatment of malignant biliary obstructive disease. Finally, we propose an algorithm that can facilitate management decisions in these patients.
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http://dx.doi.org/10.20524/aog.2020.0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315700PMC
May 2020

Palliation of dysphagia in metastatic oesogastric cancers: An international multidisciplinary position.

Eur J Cancer 2020 08 17;135:103-112. Epub 2020 Jun 17.

Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France; Univ Paris Sud, Université Paris-Saclay, F-94270, Le Kremlin-Bicêtre, France.

Malignant dysphagia is the most common symptom in advanced oesogastric cancers patients. Relief of dysphagia allows quality of life improvement, nutritional replenishment and potentially improves prognosis. Chemotherapy alone is effective and should be prioritised in patients with metastatic disease a good performance status, and its impact on dysphagia should be determined before further interventions are planned. Regarding local treatments, the insertion of a covered self-expandable metallic stent is the most commonly used alternative, as it allows for the rapid relief of severe dysphagia. Although several randomised trials have highlighted the role of oesophageal brachytherapy, this technique is often not easily accessible. Contemporary trials are ongoing to better define the role of external radiation therapy. While awaiting these results, external radiation therapy can be considered as a second-best option for patients with a life-expectancy > 3 months. It is important to offer nutritional support and to integrate quality of life measures in the palliative management of dysphagia. This multidisciplinary international position paper aims to propose a decision-making process and highlight randomised trials for the management of malignant dysphagia in metastatic oesogastric cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2020.04.032DOI Listing
August 2020

Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2).

Strahlenther Onkol 2020 Sep 12;196(9):795-804. Epub 2020 Jun 12.

1st Department of Internal Medicine, Johannes Gutenberg-University Mainz, Mainz, Germany.

Purpose: To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer.

Methods: This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable.

Results: Two-year OS was 71% in arm A (95% CI: 55-87%) vs. 53% in arm B (95% CI: 36-71%); H was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30-1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25-1.04) for progression, 0.43 (0.13-1.40) for locoregional failure, and 0.43 (0.17-1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044).

Conclusion: Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.
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http://dx.doi.org/10.1007/s00066-020-01646-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449950PMC
September 2020

Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer.

J Hepatol 2020 Nov 21;73(5):1109-1117. Epub 2020 May 21.

Division of Cancer Sciences, The University of Manchester and The Christie NHS Foundation Trust, Manchester M20 4BX, UK.

Background & Aims: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis.

Methods: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated.

Results: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 1, 2, 3 and 4 years post-trial registration were 37%, 45%, 61%, and 63%, respectively. For patients who survived 1 year, those receiving combination therapy vs. mono (p = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively).

Conclusions: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors.

Lay Summary: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.
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http://dx.doi.org/10.1016/j.jhep.2020.05.014DOI Listing
November 2020

Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research.

United European Gastroenterol J 2020 03 26;8(2):175-184. Epub 2019 Nov 26.

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.

Objectives: Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study.

Methods: Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire.

Results: Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 ± 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0-7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6-187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2-116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3-28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0-9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8-85.6) and 53.5% (50.9-56.1), respectively (OR 0.25, 95% CI 0.08-0.75,  = 0.001).

Conclusions: Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.
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http://dx.doi.org/10.1177/2050640619891580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079279PMC
March 2020

VESTIGE: Adjuvant Immunotherapy in Patients With Resected Esophageal, Gastroesophageal Junction and Gastric Cancer Following Preoperative Chemotherapy With High Risk for Recurrence (N+ and/or R1): An Open Label Randomized Controlled Phase-2-Study.

Front Oncol 2019 30;9:1320. Epub 2020 Jan 30.

University Cancer Center Leipzig, University Hospital Leipzig, Leipzig, Germany.

Perioperative chemotherapy plus surgery is one recommended standard treatment for patients with resectable gastric and esophageal cancer. Even with a multimodality treatment more than half of patients will relapse following surgical resection. Patients who have a poor response to neoadjuvant chemotherapy and have an incomplete (R1) resection or have metastatic lymph nodes in the resection specimen (N+) are especially at risk of recurrence. Current clinical practice is to continue with the same chemotherapy in the adjuvant setting as before surgery. In the phase II randomized EORTC VESTIGE trial (NCT03443856), patients with high risk resected gastric or esophageal adenocarcinoma will be randomized to either adjuvant chemotherapy (as before surgery) or to immunotherapy with nivolumab and low dose ipilimumab (nivolumab 3 mg/kg IV Q2W plus Ipilimumab 1 mg/kg IV Q6W for 1 year). The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety and toxicity, and quality of life. This is an open label randomized controlled multi-center phase-2 superiority trial. Patients will be randomized in a 1:1 ratio to study arms. The trial will recruit 240 patients; recruitment commenced July 2019 and is anticipated to take 30 months. Detailed inclusion/exclusion criteria, toxicity management guidelines, and statistical plans for EORTC VESTIGE are described in the manuscript. The trial is registered with www.ClinicalTrials.gov, identifier: NCT03443856.
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http://dx.doi.org/10.3389/fonc.2019.01320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002471PMC
January 2020

Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis?

BMC Cancer 2020 Jan 14;20(1):34. Epub 2020 Jan 14.

Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.

Objective: Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC.

Methods: Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records.

Results: Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002).

Conclusion: Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.
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http://dx.doi.org/10.1186/s12885-020-6517-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961297PMC
January 2020

Multidisciplinary management of stage II-III gastric and gastro-oesophageal junction cancer.

Eur J Cancer 2020 01 20;124:67-76. Epub 2019 Nov 20.

University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.

The aim of this manuscript is to discuss the viewpoint of the European Organisation for Research and Treatment of Cancer (EORTC) Gastric Cancer Taskforce and Japan Clinical Oncology Group (JCOG) Gastric Cancer Study Group on the current challenges in the multidisciplinary management of stage II-III gastric and gastro-oesophageal junction (GEJ) cancer. We seek to outline how these challenges are addressed in current trials of both groups. Key elements of future trials of EORTC and JCOG in this indication are described, and a joint vision on how multidisciplinary research of gastric and GEJ cancer patients should be organised is outlined.
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http://dx.doi.org/10.1016/j.ejca.2019.09.006DOI Listing
January 2020

Extended Molecular Profiling Improves Stratification and Prediction of Survival After Resection of Colorectal Liver Metastases.

Ann Surg 2019 11;270(5):799-805

Department of Gastroenterology and Hepatology, Universitätsmedizin, Mainz, Germany.

Objective: The aim of this study was to assess the effect of cancer-related genes and their mutations analyzed by next-generation sequencing (NGS) on the oncological outcome after resection of colorectal liver metastases (CRLM).

Background: Traditional prognostic scores include clinical and pathological parameters of primary tumor and metastases. The modified clinical risk score (m-CS), based on size of metastases, primary tumor nodal status, and RAS mutation status outperformed traditional scores. We hypothesized to further improve the scoring system based on the results of NGS.

Methods: Cancer tissues of 139 patients with CRLM were used for NGS. The work-up included the analysis of recurrent somatic mutations and copy number changes of 720 genes. Clinical data were extracted from a prospectively collected institutional liver database.

Results: Depending on significance, the following cancer-related genes and their alterations (%) were further investigated: APC (86%), TP53 (78%), KRAS (29%), SMAD4 (15%), PIK3CA (14%), BRAF (8%), ERBB2 (6%), SMAD3 (5%), SMAD2 (4%), and NRAS (4%). The most predictive parameters for poor oncological outcome were alterations in the SMAD family (P = 0.0186) and RAS-RAF pathway (P = 0.032). Refining the m-CS by replacing RAS with RAS-RAF pathway and adding SMAD family resulted in an extended clinical risk score which is highly predictive for oncological outcome (P < 0.0001).

Conclusion: In conclusion, mutations of the SMAD family revealed a strong prognostic effect after surgery for CRLM. Integration of alterations of the SMAD family as well as the RAS/RAF pathway resulted in a new, still simple but highly prognostic score.
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http://dx.doi.org/10.1097/SLA.0000000000003527DOI Listing
November 2019

Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors: Rationale and Current State.

Target Oncol 2019 10;14(5):505-525

Johannes-Gutenberg University, University Medical Center, Mainz, Germany.

First-line chemotherapy for many solid tumors is limited by toxicity. There is a growing interest in maintenance therapy as a strategy for prolonging the benefits of first-line therapy while minimizing toxicity. Maintenance therapy can comprise either continuation of an agent given as part of the first-line regimen (continuation maintenance) or treatment with a new agent (switch maintenance). Maintenance therapy is already established in several solid tumors, including lung, breast, gastric, colorectal, and ovarian cancer. Immune checkpoint inhibitor treatment has been shown to prolong duration of response and overall survival, but efficacy is generally restricted to a limited proportion of patients with selected tumors. Thus, efforts are ongoing to determine whether the clinical benefits of immune checkpoint inhibitors can be extended using novel treatment schedules and settings, including maintenance therapy. Early- and late-phase clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors as switch and continuation maintenance in different tumors, and a range of phase III trials are ongoing. Interpretation of results requires consideration of trial designs, eligibility criteria, and primary endpoints, in addition to biomarker exploration, and assessment of quality of life and cost effectiveness. Findings from ongoing trials will help further define the role of immune checkpoint inhibitors as maintenance therapy across a spectrum of solid tumors.
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http://dx.doi.org/10.1007/s11523-019-00665-1DOI Listing
October 2019

Late-line treatment in metastatic gastric cancer: today and tomorrow.

Ther Adv Med Oncol 2019 28;11:1758835919867522. Epub 2019 Aug 28.

Department of Internal Medicine, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.

Survival for patients with unresectable advanced or recurrent gastric cancer (GC) remains poor and the historical lack of evidence-based therapeutic options after second-line therapy is reflected in current clinical guidelines for this condition. Despite uncertainty about optimal therapeutic strategies, further treatment is appropriate for some patients after failure of second line and may prolong survival. This approach has been reported in clinical trials and is becoming more common in real-world clinical settings. Several prognostic factors may increase the likelihood that a patient will be eligible for treatment in the third-line setting, including geographic location, status at diagnosis and response to treatment. There has been little progress over the last decade until the results from two large phase III randomized controlled trials completed in the last year: the ATTRACTION-2 trial with the programmed cell death-1 (PD-1) inhibitor, nivolumab, in an Asian population; and the TAGS trial with the oral chemotherapy trifluridine/tipiracil in a global population. Both ATTRACTION-2 and TAGS reported positive results in third-line treatment in advanced GC in specific patient groups. A further recently reported study, KEYNOTE-059, which was a single-arm phase II trial of the PD-1 inhibitor pembrolizumab in a mainly non-Asian population, has provided evidence supporting the use of this immunotherapy in patients with advanced GC. As further third-line options become available, more GC patients are expected to benefit from an individualized evidence-based approach to later-line therapy, with a common goal of extending survival and improving outcomes for their refractory disease.
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http://dx.doi.org/10.1177/1758835919867522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713955PMC
August 2019

Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial.

J Cachexia Sarcopenia Muscle 2020 02 28;11(1):135-144. Epub 2019 Aug 28.

1st Medical Department, University Cancer Center Leipzig (UCCL), University Leipzig Medical Center, Leipzig, Germany.

Background: Body fat and/or muscle composition influences prognosis in several cancer types. For advanced gastric and gastroesophageal junction cancer, we investigated which body composition parameters carry prognostic information beyond well-established clinical parameters using robust model selection strategy such that parameters identified can be expected to generalize and to be reproducible beyond our particular data set. Then we modelled how differences in these parameters translate into survival outcomes.

Methods: Fat and muscle parameters were measured on baseline computed tomography scans in 761 patients with advanced gastric or gastroesophageal junction cancer from the phase III EXPAND trial, undergoing first-line chemotherapy. Cox regression analysis for overall survival (OS) and progression-free survival (PFS) included body composition parameters and clinical prognostic factors. All continuous variables were entered linearly into the model as there was no evidence of non-linear prognostic impact. For transferability, the final model included only parameters that were picked by Bayesian information criterion model selection followed by bootstrap analysis to identify the most robust model.

Results: Muscle and fat parameters formed correlation clusters without relevant between-cluster correlation. Mean muscle attenuation (MA) clusters with the fat parameters. In multivariate analysis, MA was prognostic for OS (P < 0.0001) but not for PFS, while skeletal muscle index was prognostic for PFS (P = 0.02) but not for OS. Worse performance status Eastern Cooperative Oncology Group (ECOG 1/0), younger age (on a linear scale), and the number of metastatic sites were strong negative clinical prognostic factors for both OS and PFS. MA remained in the model for OS (P = 0.0001) following Bayesian information criterion model selection in contrast to skeletal muscle index that remained prognostic for PFS (P = 0.009). Applying stricter criteria for transferability, MA represented the only prognostic body composition parameter for OS, selected in >80% of bootstrap replicates. Finally, Cox model-derived survival curves indicated that large differences in MA translate into only moderate differences in expected OS in this cohort.

Conclusions: Among body composition parameters, only MA has robust prognostic impact for OS. Data suggest that treatment approaches targeting muscle quality are unlikely to prolong OS noticeably on their own in advanced gastric cancer patients, indicating that multimodal approaches should be pursued in the future.
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http://dx.doi.org/10.1002/jcsm.12484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015239PMC
February 2020

Opinions and use of neoadjuvant therapy for resectable, borderline resectable, and locally advanced pancreatic cancer: international survey and case-vignette study.

BMC Cancer 2019 Jul 9;19(1):675. Epub 2019 Jul 9.

Department of Surgery and Liver Transplantation, Croix-Rousse University Hospital, University of Lyon, Lyon, France.

Background: Several new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC), but the support for their use for resectable, borderline resectable and locally advanced PDAC is unclear.

Methods: A survey was distributed to the members of the European-African Hepato-Pancreato Biliary Association (E-AHPBA) and the pancreas group of the European Organization for Research and Treatment of Cancer (EORTC) regarding 1) definitions of local resectability, 2) indications for neoadjuvant therapy and 3) case-vignettes regarding the resectability and treatment of PDAC.

Results: In total, 114 participants from 37 countries were registered. About 35% of respondents, each, were of the opinion that borderline resectability is defined by any venous tumor contact and venous involvement < 180° or > 180°, respectively. The majority (75.4%) of participants believed that borderline resectable PDAC has a high risk for R1 resection and that neoadjuvant therapy might increase the R0-resection rate (79.8%) and improve oncological patient selection (84.2%). Chemotherapy was regarded useful to convert locally advanced to resectable PDAC by 55.7% of respondents. In the cases with resectable, borderline resectable, and locally advanced PDAC, 10 (8.8%), 78 (68.4%), 55 (48.2%) of participants would start with chemotherapy, respectively.

Conclusions: Although definitions for borderline resectability differ among European surgeons, there seems to be a rather strong support for preoperative chemotherapy in PDAC aiming at minimizing R1 resections while increasing resection rates.
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http://dx.doi.org/10.1186/s12885-019-5889-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617881PMC
July 2019

Rational Combination of Parvovirus H1 With CTLA-4 and PD-1 Checkpoint Inhibitors Dampens the Tumor Induced Immune Silencing.

Front Oncol 2019 28;9:425. Epub 2019 May 28.

Department of Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

The recent therapeutic success of immune checkpoint inhibitors in the treatment of advanced melanoma highlights the potential of cancer immunotherapy. Oncolytic virus-based therapies may further improve the outcome of these cancer patients. A human melanoma model was used to investigate the oncolytic parvovirus H-1 (H-1PV) in combination with ipilimumab and/or nivolumab. The effect of this combination on activation of human T lymphocytes was demonstrated. Expression of CTLA-4, PD-1, and PD-L1 immune checkpoint proteins was upregulated in H-1PV-infected melanoma cells. Nevertheless, maturation of antigen presenting cells such as dendritic cells was triggered by H-1PV infected melanoma cells. Combining H-1PV with checkpoint inhibitors, ipilimumab enhanced TNFα release during maturation of dendritic cells; nivolumab increased the amount of IFNγ release. H-1PV mediated reduction of regulatory T cell activity was demonstrated by lower TGF-ß levels. The combination of ipilimumab and nivolumab resulted in a further decline of TGF-ß levels. Similar results were obtained regarding the activation of cytotoxic T cells. H-1PV infection alone and in combination with both checkpoint inhibitors caused strong activation of CTLs, which was reflected by an increased number of CD8GranB cells and increased release of granzyme B, IFNγ, and TNFα. Our data support the concept of a treatment benefit from combining oncolytic H-1PV with the checkpoint inhibitors ipilimumab and nivolumab, with nivolumab inducing stronger effects on cytotoxic T cells, and ipilimumab strengthening T lymphocyte activity.
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http://dx.doi.org/10.3389/fonc.2019.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546938PMC
May 2019